The outcome of mycobacterial infections is determined by interactions between host and bacterial factors yet only very few host factors that affect the susceptibility to the infections are known. In particular, there has been an increasing appreciation that both innate immunity and hematopoietic growth factors such as M-CSF play important roles in modulating tuberculosis.
The Ramakrishnan laboratory has established a model for mycobacterial pathogenesis using Mycobacterium marinum (Mm) in the optically transparent and genetically tractable zebrafish. This model allows us to dissect the host cellular and genetic mechanisms that regulate macrophage function during infection. We have found that zebrafish with mutations in the M-CSF-receptor, fms, are hypersusceptible to Mm. M-CSF has pleitropic effects on macrophage development and function. To determine its mechanism of resistance in infection, we performed a step-wise comparison of infection in wildtype and fms-mutant fish. We found that initial macrophage production, as well as macrophage migration to infection sites, phagocytosis and microbicidal capacity were all normal in the fms mutants. Hypersusceptibility became apparent only after granulomas had formed. We are currently testing the hypothesis that the M-CSF pathway is required for macrophage replenishment during infection to maintain granuloma integrity and retain the bacteria within a more restrictive intracellular niche. This study may shed light on the genetics of macrophage homeostasis during mycobacterial infection.